Proton generating catheters and methods for their use in enhancing fluid flow through a vascular site occupied by a calcified vascular occulation

ABSTRACT

Catheter devices and methods are provided for enhancing fluid flow through a vascular site occupied by a calcified lesion. The catheter devices of the subject invention at least include, at their distal end, a proton generating means, and in many embodiments also include a flushing means. In using the subject devices, the distal end of the catheter is placed proximal to the vascular occlusion and protons are generated, e.g., via proton generation from water, in a manner sufficient to reduce the pH of the vascular site in the region proximal to the occlusion. The subphysiologic pH is maintained for a period of time sufficient for fluid flow through the vascular site to be enhanced. Also provided are kits comprising the subject catheter devices for use in the subject methods.

TECHNICAL FIELD

The field of this invention is vascular disease, particularly vasculardiseases characterized by the presence of calcified vascular occlusions.

BACKGROUND OF THE INVENTION

Vascular occlusions, which may be partial or total occlusions, play aprominent role in many types of vascular disease. Many vascularocclusions encountered in the treatment of vascular disease arecharacterized by having a mineral component, i.e., they are calcified.Calcified vascular occlusions, both partial and total, are found in bothperipheral and coronary vascular disease A variety of differentprotocols have been developed for treating vascular diseasescharacterized by the presence of partial or total occlusions. Suchtreatment methodologies generally involve mechanical removal orreduction of the size of the occlusion, and include: bypass surgery,balloon angioplasty, mechanical debridement, atherectomy, and the like.

Despite the plethora of different treatment strategies that have beendeveloped for the treatment of vascular diseases associated withvascular occlusions, there are disadvantages associated with eachtechnique, such as tissue damage, invasiveness, etc. For example,restenosis is a common complication that results in arteries in whichocclusions have been mechanically removed.

Calcified vascular occlusions pose significant challenges to currentlyemployed treatment methodologies. For example, where the target vascularocclusion is a total occlusion, it is difficult if not impossible topass a guidewire through the occlusion, which step is required for manyof the currently used procedures. While bypass grafts are sometimesavailable as alternatives in such instances, bypass procedures havetheir own risks and complications. As such, there is continued interestin the development of endovascular methods of treating vascularocclusions. Of particular interest would be the development of methodsand devices suitable for use in the treatment of calcified vascularocclusions.

RELEVANT LITERATURE

U.S. Patents of interest include: U.S. Pat. Nos. 4,445,892; 4,573,966;4,610,662; 4,636,195; 4,655,746; 4,690,672; 4,824,436; 4,911,163;4,976,733; 5,059,178; 5,090,960; 5,167,628; 5,195,955; 5,222,941;5,370,609; 5,380,284; 5,443,446; 5,462,529; 5,496,267; 5,785,675; and5,833,650.

Catheter devices having electrodes positioned at their distal endsinclude those described in U.S. Pat. Nos. 5,997,536, 5,997,532;5,941,845; 5,938,694; 5,938,659; 5,935,124; 5,935,102; 5,935,063;5,931,835; 5,916,163; 5,916,158; 5,897,554; 5,893,885; 5,893,884;5,891,135; 5,879,295; 5,871,444; 5,860,974; 5,853,425; 5,848,972;5,843,152; 5,837,001; 5,836,990; 5,836,875; 5,827,278; 5,827,272;5,817,093; 5,814,076; 5,792,140; 5,782,898; 5,782,239; 5,779,699;5,772,590; 5,730,704; 5,718,701; and RE 35,924.

SUMMARY OF THE INVENTION

Catheter devices and methods are provided for enhancing fluid flowthrough a vascular site occupied by a calcified lesion. The catheterdevices of the subject invention at least include, at their distal end,a proton generating means, and in many embodiments also include aflushing means. In using the subject devices, the distal end of thecatheter is placed proximal to the vascular occlusion and protons aregenerated, e.g., via proton generation from water, in a mannersufficient to reduce the pH of the vascular site in the region proximalto the occlusion. The sub-physiologic pH is maintained for a period oftime sufficient for fluid flow through the vascular site to be enhanced.Also provided are kits that include the subject catheter devices for usein the subject methods.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a representation of a first catheter device according tothe subject invention.

FIG. 2 provides a representation of a second catheter device accordingto the subject invention.

FIG. 3 provides a representation of a third catheter device according tothe subject invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Catheter devices and methods are provided for enhancing fluid flowthrough a vascular site occupied by a calcified lesion. The catheterdevices of the subject invention at least include, at their distal end,a proton generating means, and in many embodiments also include aflushing means. In using the subject devices, the distal end of thecatheter is placed proximal to the vascular occlusion and protons aregenerated, e.g., via proton generation from water, in a mannersufficient to reduce the pH of the vascular site in the region proximalto the occlusion. The sub-physiologic pH is maintained for a period oftime sufficient for fluid flow through the vascular site to be enhanced.Also provided are kits that include the subject catheter devices for usein the subject methods.

In further disclosing the subject invention, the subject devices will bedescribed first in greater detail, followed by a more in depthdiscussion of the subject methods, systems and kits.

Before the subject invention is described further, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

It must be noted that as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referenceunless the context clearly dictates otherwise. Unless defined otherwiseall technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs.

Catheter Devices

As summarized above, the subject invention provides catheter devicesthat include, at their distal end, at least a proton generating means,wherein many embodiments, the devices also include a vascular siteflushing means. By catheter device is meant an elongated structure whichis capable of being introduced into and moved through the vascularsystem of a host. Typically, the subject catheter devices are elongatedtubular structures that can be introduced into the vascular site at alocation remote to a target vascular site and moved through the vascularsystem to the target site. Since they are designed to be introduced intothe vascular system of a host, the subject catheter devices havecross-sectional outer diameters ranging from about 1 mm to 5 mm, usuallyfrom about 2 mm to 3 mm, where the diameter may be constant or variedalong the length of the device. The subject catheter devices are alsocharacterized by having a distal end and a proximal end, where thedistal end is the end which is next to or at the vascular site duringuse, i.e., the end that is present inside the vascular system of thehost, and the proximal end is that end which is outside of the hostduring use, i.e., the end that is connected to a manifold, etc., duringuse.

A feature of the subject catheter devices is that they include a protongenerating means at their distal end. The proton generating means is, inthe broadest sense, any means that is capable of generating protons fromwater in the vascular site. In many embodiments, the proton generatingmeans is an electrode means for generating protons from water present inthe vascular site. In other words, the proton generating means includesan anode and a cathode which, upon application of a current, generateprotons from water in the vascular site, and thereby provide for asubphysiological pH in at least a region of the vascular site.

The electrodes that make up the anode and the cathode of the protongeneration means may be arranged at the distal end in any convenientconfiguration, so long as the configuration is capable of providing forthe requisite proton generation upon current application to theelectrodes. As such, one electrode may be a wire that passes through aring counterelectrode, two spaced apart ring electrodes may be present,etc. The distance between the cathode and the anode is sufficient toprovide for the requisite proton formation, where the distance betweenthe two electrodes typically ranges in many embodiments from about 0.1mm to 10 mm, usually from about 0.25 mm to 5 mm and more usually fromabout 0.5 mm to 2 mm. In many embodiments, the anode is positioned moredistal than the cathode, such that the anode is closer than the cathodeto the vascular occlusion during use. Representative configurations aredescribed in greater detail supra in terms of the figures.

As mentioned above, also present at the distal end of the subjectcatheters in many embodiments is a means for flushing the vascular spacewith an aqueous fluid, e.g., water, water that has one or more solutes,e.g., Na⁺, K⁺, Cl⁻, etc., such as an electrolyte solution, and the like.The flushing means typically includes an opening of a first lumenthrough which fluid leaves the catheter device and enters the vascularsite and a second opening through which fluid leaves the vascular siteand enters the catheter device, e.g., such as is found in the multilumencatheters described in PCT patent application published under thepublication number WO 00/03651 and the priority applications citedtherein, the disclosures of which priority applications are hereinincorporated by reference.

In certain embodiments, the catheter devices may include a vascularocclusion means. In these embodiments, the subject catheter devices arefurther characterized by at least including a first vascular occlusionmeans positioned at some point proximal to the distal end of the outersurface of the catheter device, e.g., the outer surface of theaspiration catheter in the coaxial embodiments described infra. Byvascular occlusion means is meant any device or component that iscapable of substantially, and preferably completely, occluding a vessel,e.g., an artery or vein. By substantially occluding is meant that fluid,e.g. blood, flow past the occlusion means upon activation is reduced byat least 95%, usually by at least 97% and more usually by at least 99%,where in preferred embodiments, fluid flow is reduced by 100% such thatthe fluid flow into the vascular site is substantially, if notcompletely, inhibited. Any convenient means may be employed, where avascular occlusion means of particular interest includes an inflatableballoon. Inflatable balloons are well known in the catheter art, and anyconvenient balloon configuration may be employed. While the inflatableballoon may be one that is designed to be inflated with a gas or liquid,of particular interest in many embodiments are those that are configuredto be inflated with a liquid, e.g. a pH elevating or buffer solution asdescribed in greater detail infra.

The catheter devices may be single integral devices or composites of twoor more disparate elements. Thus, the catheter devices may comprise allof the elements that make up the device, e.g., the electrodes, thelumens, etc., as a single structure, i.e., on a structure where no twoof these elements are capable of moving relative independently of eachother. Alternatively, the devices may be made up of two or more distinctelements that can be moved independently of each other, e.g., coaxiallumens, etc., where representative embodiments are described infra ingreater detail.

Turning now to the figures, FIG. 1 provides a depiction of the distaltip of a catheter device according to a first embodiment of the subjectinvention. Distal end 10 of the catheter device has two electrodes, theanode 15 and the cathode 13. Anode 15 and cathode 13 are ring electrodesat the end of tubular elements 16 and 14, respectively, which tubularelements are, in turn, slidably positioned inside of outer tubularelement 12. As such, tubular elements 12, 14 and 16 are coaxial and makeup the catheter device. During use, fluid is introduced into thevascular space through the opening at the distal end of element 16 inthe direction 17 and is removed from the vascular space via the annularopening 11 in the direction of the arrows. The zone 19 indicates thearea of reduced pH that is produced during use.

FIG. 2 provides a depiction of the distal tip of a catheter deviceaccording to a second embodiment of the subject invention. Distal end 20of the catheter device has two electrodes, the anode 25 and the cathode23. Anode 25 and cathode 23 are ring electrodes positioned at the end ofthe same tubular element 26, which tubular element is, in turn, slidablypositioned inside of outer tubular elements 24 and 22. As such, tubularelements 22, 24 and 26 are coaxial and make up the catheter device.During use, fluid is introduced into the vascular space through theopening at the distal end of element 26 in the direction 27 and isremoved from the vascular space via the annular opening 21 in thedirection of the arrows. The zone 29 indicates the area of reduced pHthat is produced during use.

FIG. 3 provides a depiction of the distal tip of a catheter deviceaccording to a third embodiment of the subject invention. Distal end 30of the catheter device has two electrodes, the anode 35 and the cathode33. In this embodiment, the anode 35 is a wire electrode and cathode 33is a ring electrode positioned at the end of the tubular element 36,which tubular element is, in turn, slidably positioned inside of outertubular elements 34 and 32. As such, tubular elements 32, 34 and 36 arecoaxial and make up the catheter device. During use, fluid is introducedinto the vascular space through the opening at the distal end of element36 in the direction 37 and is removed from the vascular space via theannular opening 31 in the direction of the arrows. The zone 39 indicatesthe area of reduced pH that is produced during use.

The above described specific embodiments are merely representativeembodiments of the subject catheter devices. Other configurations arepossible and are intended to come within the scope of the presentinvention.

Methods

As summarized above, also provided by the subject invention are methodsfor enhancing fluid flow through a vascular site occupied by a vascularocclusion, e.g., a partial or total occlusion. For treatment of vascularcalcified occlusions with the subject catheter devices, the subjectcatheter devices are used to generate protons in at least a region ofthe vascular site proximal to the lesion in a manner sufficient toprovide for a subphysiological pH in the region which ultimately resultsin enhancement of fluid flow through the target vascular site. Byenhanced is meant that fluid flow is either established in situationswhere fluid flow is not initially present, e.g., where the targetvascular occlusion is a total occlusion, or increased where some fluidflow through the vascular site is present, e.g., in situations where thevascular site is occupied by a partial occlusion.

The Target Vascular Site

The target site through which fluid flow is enhanced by the subjectmethods is a site within a vessel, typically an artery or vein, andusually an artery. In many embodiments, the vascular site is aperipheral vascular site, by which is meant that the vessel in which thevascular site is located is a vessel found in one of the extremities ofthe patient to be treated, i.e., the arms or legs. Often, the vascularsite is a site in a lower extremity vessel, e.g., a lower extremityartery. As indicated above, of particular interest in certainembodiments are peripheral arterial vascular sites, where specificperipheral arteries of interest include: iliac arteries, femoropoplitealarteries, irfrapopliteal arteries, femoral arteries, superficial femoralarteries, popliteal arteries, and the like. In yet other embodiments,the vascular site is present in a heart associated vessel, e.g., theaorta, a coronary artery or branch vessel thereof, etc. In yet otherembodiments, the vascular site is present in a carotid artery or abranch vessel thereof.

The vascular site is occupied by a vascular occlusion in such a mannerthat fluid flow through the vascular site, e.g., blood flow, is at leastimpeded if not substantially inhibited. By at least impeded is meantthat fluid flow is reduced by at least 20%, usually by at least 50% andmore usually by at least 80% through the vascular site as compared to acontrol. In such situations, the vascular site is occupied by a partialvascular calcified occlusion. By substantially inhibited is meant thatsubstantially no fluid flows through the vascular site. For purposes ofthis invention, fluid flow through a vascular site is considered to besubstantially inhibited where it is not possible to pass a guidewirethrough the vascular site, where the guidewire has a diameter rangingfrom 0.014 to 0.038 in and is applied to the site with a pressureranging from about 1 to 30 oz.

The Target Vascular Occlusion

The vascular occlusion that occupies the target vascular site isgenerally a calcified vascular occlusion, by which is meant that theocclusion includes at least some calcium containing component. Thecalcified occlusion may be a substantially pure mineral structure, ormay be a more complex formation that includes both mineral and othercomponents, including organic matter, e.g., lipids, proteins, and thelike. As mentioned above, the target vascular occlusion may be a partialor total vascular occlusion.

The mineral component making up the calcified lesion is generally madeup of one or more calcium phosphates, where the calcium phosphates aregenerally apatitic. The mineral component of the calcified occlusiontypically includes one or more of hydroxyapatite, carbonatedhydroxyapatite (dahllite) and calcium deficient hydroxyapatite.

In addition to the mineral component, the calcified occlusion thatoccupies the target vascular site may also comprise one or moreadditional components, where such components include: lipids;lipoproteins; proteins; including fibrinogen, collagen, elastin and thelike; proteoglycans, such as chondroitin sulfate, heparin sulfate,dermatans, etc.; and cells, including smooth muscle cells, epithelialcells, macrophages and lymphocytes. As such, calcified occlusions thatare targets of the subject methods include those that may be describedas: type IV, type V and type VI lesions, as defined in Stary et al.,Arterioscler. Thromb. Vasc. Biol. (1995)15:1512-1531.

In the vascular occlusions that occupy the target vascular sites of manyembodiments of the subject methods, the mineral component of thecalcified occlusion generally makes up from about 10 to 100, usuallyfrom about 10 to 90 and more usually from about 10 to 85 dry weight % ofthe occlusion. The size of the occlusion that is the target of thesubject methods varies depending on location and specific nature of theocclusion. Generally, the volume of the occlusion ranges from about 20to 10,000 mm³, usually from about 30 to 500 mm³ and more usually fromabout 50 to 300 mm³.

In certain embodiments, one or both ends of the occlusion may becharacterized by being primarily thrombotic material, e.g., a thrombus,where the thrombotic domain of the occlusion extends for about 1 to 5cm. The nature of the thrombotic domain may be organized ordisorganized.

Fluid Flow Enhancement

In the subject methods, fluid flow is enhanced through the vascular siteby generating protons in the vascular site in a manner sufficient toprovide for a region of subphysiological pH at least proximal to thecalcified vascular occlusion. Protons may be generated using anyconvenient protocol, where one protocol of interest is to generate theprotons from water present in the vascular site by electrode means,i.e., with an anode and a cathode. In the subject methods, protons aregenerated in the region of the vascular site next to or adjacent to thelesion such that the pH of this region is generally less than about 6,usually less than about 4 and in many embodiments less than about 2,where in certain embodiments the pH in this region during practice ofthe subject methods does not exceed about 1.

When an anode and a cathode are employed to generate the protons andthereby provide for the region of subphysiologic pH, an electricpotential is applied between the two electrodes, where the magnitude ofthe electric potential is sufficient to provide for the requisite protongeneration from water. The magnitude of the electric potential that isapplied between the two electrodes, i.e., the anode and the cathode,typically ranges from about 1 V to 10 V, usually from about 1 V to 3 Vand more usually from about 1.3 V to 2 V. Any convenient means forapplying the electric potential between the two electrodes may beemployed, where means of interest include direct current (DC) means andalternating current (AC) means, as well as pulsed current means. Theparticular means chosen will depend primarily on the particular protocolemployed and the specific nature of proton generation desired.

While in certain embodiments the requisite protons are generated fromwater present in the vascular site, e.g., plasma present in the vascularsite, in many preferred embodiments of the subject invention, thevascular site is flushed with an aqueous fluid concomitant with protongeneration so as to provide for a constant source of water to be used inproton generation and to remove fluid and debris, including dissolvedand/or particulate calcium phosphate mineral, from the vascular site.

Is these embodiments that include flushing the vascular site with anaqueous fluid, it is preferred that the pressure in the localenvironment which includes the surface of the occlusion, i.e., the areabounded by the vessel walls, the surface of the target occlusion and thecatheter system used to deliver the solution, remains substantiallyisobaric. By substantially isobaric is meant that the pressure in thelocal environment does not vary by a significant amount, where theamount of variance over the treatment period does not vary by more thanabout 50%, usually by not more than about 10% and more usually by notmore than about 5%. In other words, the local environment remainssubstantially isobaric during the treatment period. Accordingly, wherefluid is dynamically contacted with the surface of the target occlusion,fluid is also simultaneously removed from the local environmentcomprising the surface of the target occlusion, such that the overallvolume of fluid in the local environment remains substantially constant,where any difference in volume at any two given times during thetreatment period does not exceed about 50%, and usually does not exceedabout 10%. As such, the aqueous fluid is introduced into the localenvironment of the target lesion in a manner such that the localenvironment remains substantially isovolumetric.

A variety of different types of aqueous fluids may be employed in thesubject methods. The term aqueous fluid is used broadly to refer to notonly pure water, e.g., water for injection or WFI, but also water thatincludes one or more distinct solutes, e.g., electrolytes. As such, theterm aqueous fluid also includes electrolyte solutions. Electrolyte orsalt solutions of interest include NaCl solutions, e.g., phosphatebuffered saline, and other physiologically acceptable analogous saltsolutions, as are known in the art, and the like.

When employed, the aqueous fluid is introduced in a manner such that theflow rate of the fluid through the vascular site of the lesion isgenerally at least about 10 cc/min, usually at least about 20 cc/min andmore usually at least about 60 cc/min, where the flow rate may be asgreat as 120 cc/min or greater, but usually does not exceed about 1000cc/minute and more usually does not exceed about 500 cc/minute, where by“volume” is meant the local environment of the occlusion, as definedabove. The total amount of fluid that is passed through the localenvironment of the lesion during the treatment period typically rangesfrom about 100 to 1000 cc, usually from about 200 to 800 cc and moreusually from about 400 to 500 cc. The solution is generally pressurizedto achieve the desired flow rate, as described supra. As such, thepressure at the proximal end of the coaxial catheter assembly throughwhich the solution enters the catheter and is thereby introduced intothe local environment typically ranges from about 50 to 1200 psi,usually from about 100 to 600 psi and more usually from about 200 to 400psi. It is important to note that in many embodiments of the subjectinvention the overall pressure in the local environment is maintained atsubstantially isometric or isobaric conditions. As such, the negativepressure at the entrance to the aspiration catheter, e.g., the openannulus at the distal end of the aspiration catheter will be ofsufficient magnitude to provide for substantially isobaric conditions.Preferably, the overall pressure in the local environment is maintainedat a value ranging from about 0.1 to 3 psi, usually from a bout 0.5 to2.5 psi and more usually from about 1 to 2 psi. This lower, isobaricpressure is maintained through proper control of the flow rate into andout of the local site, e.g., through proper control of fluidintroduction and aspiration.

Time Period

In the subject methods, the subphysiologic pH is maintained in thevascular site, e.g., through proton generation in the vascular site, fora period of time sufficient for fluid flow to be enhanced or establishedthrough the vascular site, e.g., established or improved. As such, wherethe target occlusion is a total occlusion, subphysiologic pH ismaintained for a period of time sufficient for a guidewire to be passedthrough the vascular site, as described above. Alternatively, where thetarget occlusion is a partial occlusion, subphysiologic pH is maintainedfor a period of time sufficient for the rate of fluid flow to beincreased through the vascular site, generally by at least about 10%,usually by at least about 50%, and in many embodiments by at least about100%. Generally, the period of time during which subphysiologic pH ismaintained proximal to the target occlusion ranges from about 5 to 100minutes, usually from about 10 to 30 minutes.

Further Embodiments of the Subject Methods

In a number of embodiments of the subject methods, the above describedbasic methods may be modified to include a number of additional methodsteps. Additional method steps that may be present in the overallprocess include: rendering the local environment of the target occlusionbloodless, washing or rinsing the local environment of the targetocclusion, applying external energy to the target occlusion; imaging thetarget vascular site; establishing or expanding a passageway through aninitial thrombotic domain of the target occlusion; and the like.

Rendering the Local Environment Bloodless

In certain embodiments, as described above, the local environment of thetarget occlusion is rendered substantially bloodless prior tointroduction of the aqueous fluid. In these embodiments, the balloon(s)of the assembled catheter system is inflated to physically isolate thelocal environment from the remainder of the circulatory system and thenthe local environment is flushed with a physiologically acceptablesolution, such that substantially all of the blood present in thesolution is removed. Typically, a washing solution will be employed inthis step of rendering the local environment bloodless. Examples ofwashing solutions that may find use in these embodiments include: waterfor injection, saline solutions, e.g., Ringer's, phosphate bufferedsaline, or other physiologically acceptable solutions. The washingsolution includes an anticlotting factor in many embodiments, whereanticlotting factors of interest include heparin and the like. Thewashing solution can also contain chelating agents.

Application of External Energy

In certain embodiments, external energy is applied to the vascular siteto promote mechanical break-up of the occlusion into particles or debristhat can be easily removed from the vascular site. Any means of applyingexternal energy to the vascular site may be employed. As such, jets orother such means on a catheter device which are capable of providingvarying external forces to the occlusion sufficient to cause theocclusion to break up or disrupt the occlusion may be employed. Ofparticular interest in many embodiments is the use of ultrasound. Theultrasound can be applied during the entire time of contact of thecardiovascular tissue with the acidic treatment solution, or theultrasound can be applied for only part of the treatment period. In oneembodiment, ultrasound is applied for several short periods of timewhile the dissolution treatment solution is contacted with the targetocclusion. There are several devices for the application of ultrasoundto cardiovascular tissue known to those of skill in the art. See e.g.U.S. Pat. No. 4,808,153 and U.S. Pat. No. 5,432,663, the disclosures ofwhich are herein incorporated by reference.

In such methods where external energy is applied to the occlusion inorder to disrupt or break-up the occlusion into particles or debris, theparticles or debris may range in size from about 0.01 to 4.0 mm, usuallyfrom about 0.1 to 2.0 mm and more usually from about 0.5 to 1.0 mm. Insuch instances, the method may further include a step in which theresultant particles are removed from the vascular site. Particles may beremoved from the vascular site using any convenient means, such as thecatheter of the subject invention described in greater detail infra.

Another means that may be employed to apply external energy to thelesion during the dissolution process is to use a mechanical means ofapplying external energy. Mechanical means of interest include movingstructures, e.g., rotating wires, guidewires, which physically contactthe target occlusion and thereby apply physical external energy to thetarget lesion.

Imaging

In addition, it may be convenient to monitor or visualize the vascularsite prior to or during treatment. A variety of suitable monitoringmeans are known to those of skill in the art. Any convenient means ofinvasive or noninvasive detection and/or quantification may be employed.Such means include plain film roentgenography, coronary arteriography,fluoroscopy, including digital subtraction fluoroscopy,cinefluorography, conventional, helical and electron beam computedtomography, intravascular ultrasound (IVUS), magnetic resonance imaging,transthoracic and transesophageal echocardiography, rapid CT scanning,antioscopy and the like. Any of these means can be used to monitor thevascular site before, during or after proton generation in the vascularsite.

Thrombus Removal Step

The subject methods may further include a thrombus removal step, e.g.,where the calcified domain of the target occlusion is covered by athrombotic domain, as described above. In such methods, any thrombusremoval means that is capable of providing sufficient access of theeelectrode assembly and protons generated thereby to the surface thecalcified domain of the target lesion may be employed. Thus, where thethrombotic domain is a disorganized domain, it may be sufficient to passincreasingly larger diameter guidewires through the domain until apassageway of sufficient width to provide access of the catheterassembly described above to the surface of the occlusion is established.Alternatively, portions of the thrombotic domain may be removed, e.g.,via atherectomy methods, angioplasty methods, and the like, wheredevices for performing such procedures are known to those of skill inthe art. See the patent references cited in the Relevant Literaturesection, supra, which references are herein incorporated by reference.

In yet other embodiments, the thrombus may be removed with RF ablationusing techniques known to those of skill in the art. The RF ablation maybe effected by using the proton generating electrodes to provide RFcutting action, e.g., by alternating application of a proton generatingcurrent to the electrodes with application of RF to the electrodes, orby using a separate set of RF electrodes present in the catheter device.RF devices and methods for their use are described in U.S. Pat. Nos.6,059,778; 6,050,994; 6,015,407; 5,865,788; 5,807,395; 5,785,705;5,720,718; 5,545,161; 5,423,811; 5,348,554; 5,098,431; and 4,936,281;the disclosures of which are herein incorporated by reference.

Outcome

As discussed above, the subject methods result in the enhancement offluid flow through the vascular site occupied by the occlusion. Fluidflow is considered to be enhanced in those situations where the vascularsite is totally occluded when a guide wire can be moved through thevascular site without significant resistance. Fluid flow is consideredto be enhanced in those situations in which the vascular site ispartially occluded when the rate of fluid flow through the vascular siteincreases by at least 10%, usually by at least 50% and in manyembodiments by at least 100%.

In certain embodiments, the subject methods will not result in completeremoval of the target occlusion from the vascular site. As such, thevascular site, while not totally occluded, may still include lesiondeposits on the wall which impede fluid flow through the vascular siteand the removal or reduction of which is desired. Any convenientprotocol for treating these remaining deposits may be employed, e.g.,balloon angioplasty, atherectomy, stenting, etc.

Systems

Also provided by the subject invention are systems for practicing thesubject methods, i.e., for enhancing fluid flow through a vascular siteoccupied by a vascular occlusion. The subject systems at least includethe catheter systems as described above, a manifold, a fluid reservoirfor storing aqueous fluid and a negative pressure means for providingaspiration or suction during use of the system. The systems may furtherinclude a number of optional components, e.g., guidewires, pumps forpressurizing fluids, and the like. See e.g., U.S. patent applicationSer. No. 09/384,860, the disclosure of which is herein incorporated byreference.

Utility

The subject devices and methods find use in a variety of differentapplications in which it is desired to enhance fluid flow, usually bloodflow, (or at least pass a guidewire through), a vascular site that isoccupied by a calcified vascular occlusion, e.g., a partial or totalocclusion. As such, the subject methods and devices find use in thetreatment of peripheral vascular disease, etc. The subject methods alsofind use in the treatment of coronary vascular diseases. By treatment ismeant that a guidewire can at least be passed through the vascular siteunder conditions which, prior to treatment, it could not. Treatment alsoincludes situations where the subject methods provide for larger fluidpassageways through the vascular site, including those situations wherefluid flow is returned to substantially the normal rate through thevascular site. The subject methods may be used in conjunction with othermethods, including balloon angioplasty, atherectomy, and the like, aspart of a total treatment protocol.

A variety of hosts are treatable according to the subject methods.Generally such hosts are “mammals” or “mammalian,” where these terms areused broadly to describe organisms which are within the class mammalia,including the orders carnivore (e.g., dogs and cats), rodentia (e.g.,mice, guinea pigs, and rats), lagomorpha (e.g. rabbits) and primates(e.g., humans, chimpanzees, and monkeys). In many embodiments, the hostswill be humans.

ADDITIONAL UTILITY

The subject devices also find use in methods of preventing restinosis,as described in U.S. Pat. No. 6,156,350, the disclosure of which isherein incorporated by reference. In the methods U.S. Pat. No.6,156,350, a vascular site of a host is contacted with a solution havinga sub-physiologic pH, e.g. a solution having a pH of less than about 4.The vascular site is contacted with the solution of reduced pH for aperiod of time sufficient for at least the progression of restenosis atthe vascular site to at least be slowed, if not prevented. The catheterdevices of the present invention can be employed to create the solutionof sub-physiologic pH at the vascular site and therefore preventrestinosis according to the methods of U.S. Pat. No. 6,156,350.

Kits

Also provided by the subject invention are kits for use in enhancingfluid flow through a vascular site occupied by an occlusion. The subjectkits at least include a catheter device or system, as described above.The kits may further include one or more additional components andaccessories for use with the subject catheter systems, including tubingfor connecting the various catheter components with fluid reservoirs,syringes, pumping means, etc., connectors, one or more guidewires,dilators, vacuum regulators, etc. Other elements that may be present inthe subject kits include various components of the systems, includingmanifolds, balloon inflation means, e.g., syringes, pumping means,negative pressure means etc.

Finally, the kits include instructions for practicing the subjectmethods, where such instructions may be present on one or more of thekit components, the kit packaging and/or a kit package insert.

The following examples are offered by way of illustration and not by wayof limitation.

Experimental

-   I. A 50 year old male having a total occlusion in the superficial    femoral is treated as follows.-   1. The patient is heparinized using standard procedures.-   2. An introducer sheath is placed either in the same leg to provide    retrograde access or in the opposite leg to provide cross-over    access.-   3. A guidewire is inserted and advanced to the site of the total    occlusion.-   4. The catheter device depicted in FIG. 1 is inserted so that the    distal end of the device is at the vascular site occupied by the    total occlusion.-   5. Contrast medium is then injected into the vascular site to    confirm the location of the distal end of the catheter.-   6. A sufficient amount of heparinized phosphate buffered saline is    then injected through port into the vascular site or local    environment and aspirated therefrom such that the local environment    is rendered substantially bloodless.-   7. An constant electric potential provided by an electrically    connected DC source is then applied between the anode and cathode    such that protons are generated in the vascular site and the pH of    the vascular site at least proximal to the occlusion is decreased    to 1. Concomitantly, a sodium chloride electrolyte solution is    flushed through the vascular site.-   8. As the occlusion is demineralized, the catheter insert is    advanced independent of the aspiration catheter.-   9. Once a passage through the occlusion sufficient to pass a    guidewire through the occlusion is produced, the device is removed.

The above procedure results in fluid flow through the vascular siteoccupied by the lesion being reestablished, as evidenced by passing aguidewire through the vascular site.

It is evident from the above discussion and results that improvedmethods of enhancing blood flow through a vascular occlusion areprovided. Specifically, the subject invention provides a means forreadily establishing fluid flow through a vascular site totally occludedby a calcified vascular occlusion, which has heretofore been difficultto practice. As such, the subject invention provides a means for usingless traumatic procedures for treating peripheral vascular disease,thereby delaying or removing the need for graft procedures and/oramputation. A critical feature of the subject devices and methods isthat a simple catheter based device is employed, thereby providing foreconomical manufacture of the device and ease of use. As such, thesubject invention represents a significant contribution to the field.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1. A catheter device comprising at its distal end: a proton generatingmeans; and a vascular site flushing means.
 2. The catheter deviceaccording to claim 1, wherein said vascular site flushing meanscomprises: a fluid introduction means; and a fluid aspiration means. 3.The catheter device according to claim 1, wherein said proton generatingmeans is an electrode means.
 4. The catheter device according to claim3, wherein said electrode means comprises: an anode; and a cathode. 5.The catheter device according to claim 1, wherein said catheter devicecomprises at least two distinct elements which are movable relative toeach other.
 6. The catheter device according to claim 4, wherein saidcatheter device further comprises a means for applying an electricpotential between said cathode and said anode.
 7. A catheter devicecomprising at its distal end: a proton generating means comprising ananode and a cathode; a fluid introduction means; and an aspirationmeans.
 8. The catheter device according to claim 7, wherein saidcatheter device comprises at least two distinct elements which aremovable relative to each other.
 9. The catheter device according toclaim 7, wherein said catheter device further comprises a means forapplying an electric potential between said cathode and said anode. 10.The catheter device according to claim 7, wherein said catheter devicefurther comprises a vascular occlusion means.
 11. A method of enhancingfluid flow through a vascular site occupied by a vascular occlusion,said method comprising: (a) generating protons from water in saidvascular site in a manner sufficient to provide for a subphysiologicalpH in said vascular site; and (b) maintaining said subphysiological pHin said vascular site for a period of time sufficient for fluid flow tobe enhanced through said vascular site; whereby fluid flow is enhancedthrough said vascular site.
 12. The method according to claim 11,wherein said method further comprises flushing said vascular site withan aqueous solution.
 13. The method according to claim 12, wherein saidaqueous solution is an electrolyte solution.
 14. The method according toclaim 12, wherein said protons are generated by electrolyzing water insaid vascular site.
 15. The method according to claim 11, wherein saidvascular occlusion comprises calcium.
 16. The method according to claim11, wherein said occlusion is a total occlusion.
 17. The methodaccording to claim 11, wherein said occlusion is a partial occlusion.18. The method according to claim 11, wherein a catheter deviceaccording to claim 1 is used to generate protons in said vascular site.19. A system for enhancing fluid flow through a vascular site occupiedby a vascular occlusion, said system comprising: (a) a catheter deviceaccording to claim 1; (b) a manifold; (c) an aqueous fluid reservoir;and (d) a source of negative pressure.
 20. The system according to claim19, wherein said system further comprises a guidewire.
 21. A kit for usein enhancing fluid flow through a vascular site occupied by a vascularocclusion, said kit comprising: a catheter device according to claim 1.22. The kit according to claim 21, wherein said kit further comprises aguidewire.